Biology subjects

Dequiedt, F.

Publications and source records attributed to Dequiedt, F..

7 recordsLinked to original sources

bioRxiv2026

FET fusion proteins reshape splicing factor networks to drive oncogenic alternative splicing

Gene fusions involving the FET gene family (FUS, EWSR1, and TAF15) act as drivers of numerous cancer subtypes. The resulting chimeric proteins are widely viewed as aberrant transcriptional regulators that promote malignant transformation through chromatin and enhancer reprogramming. Here, we show that FET fusion oncoproteins also function as regulators of alternative splicing across multiple sarcoma subtypes. Transcriptomic analyses revealed extensive but largely non-overlapping splicing programs driven by the EWSR1::FLI1, EWSR1::WT1, EWSR1::ATF1 and FUS::DDIT3 fusions that nevertheless converged on common oncogenic functions. Fusion-dependent splicing regulation was mechanistically separable from canonical transcriptional activity and was associated with extensive remodeling of cooperative RNA-binding protein (RBP) assemblies on target transcripts. Despite regulating distinct exons, different FET fusions engaged highly similar RBP interaction networks, consistent with a conserved mode of splicing regulation. Transcriptome-wide mapping of RBP occupancy revealed extensive reorganization of local RNA regulatory landscapes following fusion depletion. The requirement of RNA for FET fusion condensate formation, together with the inability of condensation-defective mutants to restore splicing regulation, further supported a role for higher-order assemblies in fusion-dependent alternative splicing (AS) control. Fusion-driven splicing programs stratified Ewing sarcoma patients independently of established clinical covariates, thereby underscoring their clinical relevance. AS of TFDP1 emerged as a common fusion-regulated splicing event required for sarcoma cell fitness and therapeutically actionable using antisense oligonucleotides. Together, our findings establish AS regulation as a conserved function of FET fusion oncoproteins that is mechanistically separable from their canonical transcriptional activity. More broadly, they support a model in which oncogenic fusion proteins can drive malignant phenotypes through large-scale remodeling of RNA regulatory networks.

molecular biology↗

bioRxiv2026

Coordinated Temporal Dynamics of Glucocorticoid Receptor Binding and Chromatin Landscape Drive Transcriptional Regulation

Glucocorticoid receptor (GR) signaling elicits diverse transcriptional responses through dynamic and context-dependent interactions with chromatin. Here, we define a temporally resolved and mechanistically integrated framework for GR-mediated gene regulation. Time-resolved analyses identify three conserved classes of GR chromatin binding (sustained, transient, and late), distinguished by differences in motif strength, chromatin accessibility, and cofactors engagement. Early GR binding preferentially occurs at high-affinity glucocorticoid response elements (GREs) within pre-accessible regulatory regions, whereas late binding is associated with weaker motifs and requires chromatin remodeling activity. Enhancer activation, marked by H3K27ac deposition, closely tracks GR occupancy, supporting a model in which GR recruits acetyltransferase activity to drive coordinated enhancer activation. Concurrently, GR-centered interaction networks are dynamically reconfigured, and motif enrichment analyses identify distinct transcription factor signatures across binding classes, including AP-1/JUNB at transient sites and CEBP family members at late-binding regions. Integration of chromatin binding, chromatin interaction, and transcriptomic datasets reveals that temporal and combinatorial GR occupancy is functionally linked to gene expression programs. Distinct GR binding clusters are nonrandomly associated with specific transcriptional trajectories, including sustained, transient, and late gene induction. Moreover, combinatorial occupancy across multiple regulatory elements correlates quantitatively with transcriptional output, indicating that GR functions not as a simple binary regulator, but as an integrator of multilayered regulatory inputs. These findings support a unified model in which temporal binding dynamics, chromatin state, and combinatorial enhancer activity collectively encode transcriptional specificity, providing a general framework for stimulus-responsive nuclear receptor signaling.

molecular biology↗

bioRxiv2024

Transcription factors form a ternary complex with NIPBL/MAU2 to localize cohesin at enhancers

While the cohesin complex is a key player in genome architecture, how it localizes to specific chromatin sites is not understood. Recently, we and others have proposed that direct interactions with transcription factors lead to the localization of the cohesin-loader complex (NIPBL/MAU2) within enhancers. Here, we identify two clusters of LxxLL motifs within the NIPBL sequence that regulate NIPBL dynamics, interactome, and NIPBL-dependent transcriptional programs. One of these clusters interacts with MAU2 and is necessary for the maintenance of the NIPBL-MAU2 heterodimer. The second cluster binds specifically to the ligand-binding domains of steroid receptors. For the glucocorticoid receptor (GR), we examine in detail its interaction surfaces with NIPBL and MAU2. Using AlphaFold2 and molecular docking algorithms, we uncover a GR-NIPBL-MAU2 ternary complex and describe its importance in GR-dependent gene regulation. Finally, we show that multiple transcription factors interact with NIPBL-MAU2, likely using interfaces other than those characterized for GR.

molecular biology↗

bioRxiv2021

Interactome and structural basis for targeting the human T-cell leukemia virus Tax oncoprotein

Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Although ATL is a well-characterized T-cell neoplasm, linked to intermittent expression of the viral Tax-1 protein, there is currently no strategy to target Tax-1 functions using small molecules. Here, we report a comprehensive interaction map between Tax-1 and human PDZ domain-containing proteins (hPDZome). We show that Tax-1 interacts with more than one-third of hPDZome components, including proteins involved in cell cycle, cell-cell junctions, cytoskeleton organization, and membrane complex assembly. Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the structural basis of the interaction between the C-terminal PDZ binding motif (PBM) of Tax-1, and the PDZ domains of syntenin-1, an evolutionary conserved hub that controls exosome trafficking. Finally, we have used confocal imaging, molecular modelling, NMR and mammalian cell-based assays to demonstrate that the Tax-1/syntenin-1 interaction is amenable to small-molecule inhibition. Altogether, our study highlights the biological significance of Tax-PDZ interactome and its interplay with exosome formation. It shows a direct link between extracellular vesicles and HTLV-1 transmission, providing a novel framework for the design of targeted therapies for HTLV-1-induced diseases.

biochemistry↗

bioRxiv2021

The viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape

While viral infections are known to hijack the transcription and translation of the host cell, the extent to which encoded viral proteins coordinate these perturbations remains unclear. Here we demonstrate that the oncoviral proteins Tax and HBZ interact with specific components of the spliceosome machinery, including the U2 auxiliary factor large subunit (U2AF2), and the complementary factor for APOBEC-1 (A1CF), respectively. Tax and HBZ perturb the splicing landscape in T-cells by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia (ATL) patients, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinately used by Tax and HBZ to reprogram the transcriptome. HighlightsO_LITax and HBZ interact with RNA-binding proteins as well as transcription factors C_LIO_LIHTLV-1 encoded proteins Tax and HBZ alter the splicing landscape in T-cells C_LIO_LITax and HBZ expression affect alternative splicing of 33 and 63 cancer genes, respectively C_LIO_LIOpposing roles for Tax and HBZ in deregulation of gene expression C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/427104v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@b5f6f0org.highwire.dtl.DTLVardef@6725b3org.highwire.dtl.DTLVardef@1dc32fborg.highwire.dtl.DTLVardef@19728c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2020

Exostosin-1 Glycosyltransferase Regulates Endoplasmic Reticulum Architecture and Dynamics

The endoplasmic reticulum (ER) is a central eukaryotic organelle with a tubular network made of hairpin proteins linked by hydrolysis of GTP nucleotides. Among post-translational modifications initiated at the ER level, glycosylation is the most common reaction. However, our understanding of the impact of glycosylation on ER structure remains unclear. Here, we show that Exostosin-1 (EXT1) glycosyltransferase, an enzyme involved in N-glycosylation, is a key regulator of ER morphology and dynamics. We have integrated multi-omics data and super-resolution imaging to characterize the broad effect of EXT1 inactivation, including ER shape-dynamics-function relationships in mammalian cells. We have observed that, inactivating EXT1 induces cell enlargement and enhances metabolic switches such as protein secretion. In particular, suppressing EXT1 in mouse thymocytes causes developmental dysfunctions associated to ER network extension. Our findings suggest that EXT1 drives glycosylation reactions involving ER structural proteins and high-energy nucleotide sugars, which might also apply to other organelles.

cell biology↗

bioRxiv2020

The cytoskeleton adaptor protein Sorbs1 controls the development of lymphatic and venous vessels in zebrafish

Lymphangiogenesis, the formation of lymphatic vessels is tightly linked to the development of the venous vasculature, both at the cellular and molecular levels. Here, we identify a novel role for Sorbs1, the founding member of the SoHo family of cytoskeleton adaptor proteins, in vascular and lymphatic development in zebrafish. We show that Sorbs1 is required for secondary sprouting and emergence of several vascular structures specifically derived from the axial vein. Most notably, formation of the precursor parachordal lymphatic structures is affected in sorbs1 mutant embryos, severely impacting the establishment of a proper trunk lymphatic network and leading to edema development. We show that Sorbs1 is probably not part of the Vegfc signaling, but instead might interacts with the BMP pathways. Mechanistically, we show that Sorbs1 controls FAK/Src signaling to impact on Rac1 and RhoA GTPases-regulated cytoskeleton processes. Inactivation of Sorbs1 altered cell-extracellular matrix (ECM) contact rearrangement and cytoskeleton dynamics, leading to specific defects in endothelial cell migratory and adhesive properties. Our data thus establish Sorbs1 as an important regulator of lymphangiogenesis distinct from the Vegfc signaling axis, increasing our understanding of context-specific vascular and lymphatic development.

developmental biology↗